title: Augmented renal prostacyclin by intrarenal bicistronic cyclo-oxygenase-1/prostacyclin synthase gene transfer attenuates renal ischemia-reperfusion injury.
abstract: BACKGROUND
  We elucidated the protective mechanism of increased prostacyclin (PGI2) derived from adenoviral cyclo-oxygenase (COX)-1/prostacyclin synthase (PGIS) (Adv-COPI) gene transfer in rat kidneys with ischemia-reperfusion (I/R) injury.
  
  
  METHODS
  We tended to augment PGI2 production by intrarenal arterial Adv-COPI administration with renal venous clamping in female Wistar rats. After Adv-COPI transfection, we evaluated the renal COX-1 and PGIS protein expression and PGI2 and prostaglandin E2 (PGE2) levels in the kidney and renal venous plasma. We evaluated the protective effect of PGI2 on hypoxia/reoxygenation-induced tubular cells injury or I/R kidneys by measuring oxidative stress, necrosis, apoptosis, and autophagy in tubules and kidneys and determining renal function, microcirculation, and accumulation of tubular 4-hydroxynonenal in the kidney in vivo.
  
  
  RESULTS
  Adv-COPI treatment selectively augmented COX-1 and PGIS protein expression in the renal proximal and distal tubules and significantly increased PGI2, not PGE2, production in the renal venous plasma and kidney at the baseline level. I/R markedly depressed renal blood flow and increased the production in O2, PGE2, the expression in P47 and Rac-1 expression of two nicotinamide adenine dinucleotide phosphate oxidase subunits, cytosolic cytochrome C release, proapoptotic marker lamin expression, the pathologic appearance of necrosis, apoptosis, and autophagy, and blood urea nitrogen and creatinine levels in the damaged kidneys. Adv-COPI protected distal and proximal tubules against hypoxia/reoxygenation-enhanced oxidative stress and autophagic, apoptotic, and necrotic cell death. Adv-COPI significantly improved renal function by restoring renal blood flow, reducing nicotinamide adenine dinucleotide phosphate oxidase-derived and mitochondria-derived oxidative stress, and necrosis, apoptosis, and autophagy.
  
  
  CONCLUSIONS
  Increased PGI2 by Adv-COPI protects the kidney against I/R-induced oxidative stress, necrosis, apoptosis and autophagy.
authors.affiliation: 1 Bureau of Planning, Department of Health, Executive Yuan, Taipei, Taiwan. 2 Department of Internal Medicine, National Yang-Ming University, Taipei, Taiwan. 3 Department of General Surgery, Far-East Memory Hospital, New Taipei City, Taiwan. 4 Department of Internal Medicine, Far-East Memory Hospital, New Taipei City, Taiwan. 5 Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. 6 Address correspondence to: Chiang-Ting Chien, Ph.D., Department of Life Science, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road, Taipei City 11677, Taiwan or Shih-Ping Hsu, M.D., Ph.D., Department of Internal Medicine, Far-East Memory Hospital, No. 21, Section 2, Nanya S. Road, Banciao District, New Taipei City 220, Taiwan.
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Yang
authors.forename: Kuo-Hsin
authors.initials: KH
authors.lastname: Chen
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Hsu
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chien
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D003404:Creatinine / Q000737:chemistry; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D009336:Necrosis; D009584:Nitrogen / Q000737:chemistry; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000628:therapy*
chemical_list: D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone; D009584:Nitrogen; D010100:Oxygen